GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 135Gene Ther Mol Biol Vol 7, 135-151, 2003Gene therapy for vascular diseasesReview ArticleSarah J. George 1 , Filomena de Nigris 2 , Andrew H. Baker 3 , Claudio Napoli 4,51 Bristol Heart Institute, University of Bristol, Bristol, BS2 8H, UNITED KINGDOM; 2 Department of PharmacologicalSciences, University of Salerno, 84084 Italy; 3 Division of Cardiovascular and Medical Sciences, University of Glasgow,Western Infirmary, Glasgow G11 6NT, UNITED KINGDOM; 4 Departments of Medicine and Clinical Pathology,University of Naples, Naples 80131, Italy; 5 Department of Medicine-0682, University of California San Diego, CA92093,USASJ George and F de Nigris contributed equally to this review.__________________________________________________________________________________*Correspondence: Claudio Napoli, MD, PhD, FACA, PO BOX 80131, Naples, Italy, e-mail: claunap@tin.itKey words: Atherosclerosis, gene therapy, adenoviruses, vascular diseases.Received: 2 July 2003; Accepted: 18 July 2003; electronically published: July 2003SummaryCurrently, successful pharmacological treatments are unavailable for many vascular diseases. Many patientsundergo surgical interventions and then present with recurrence of symptoms. Recently, gene therapy using bothnon-viral and viral delivery has emerged as a novel tool to treat patients with vascular diseases. Here we discuss therequirement to develop suitable gene delivery vectors for vascular diseases. Our expanding knowledge of thepathogenesis of vascular diseases has allowed the identification of several gene therapy strategies and manycandidate genes. Gene therapy using both gene knockout and gene overexpression has been considered. In preclinicalstudies, antisense and decoy oligonucleotides have been successfully employed to knockout the expression ofstimulatory genes such as cell cycle promoters and growth factors. Furthermore, overexpression of inhibitory genessuch as cell cycle inhibitors and nitric oxide and overexpression of genes to promote therapeutic angiogenesis havebeen shown potential in animal models. The progress of pre-clinical studies to treat vein graft failure, restenosis,myocardial and peripheral ischemia and hypertension and the development of clinical trials will be discussed.Despite the quite promising findings with clinical trials, particularly with therapeutic angiogenesis, improved genetransfer vectors and methods for safe long-term gene transfer are still required to bring gene therapy to clinicalpractice.I. IntroductionGene therapeutics have been proposed as a potentialnovel therapy for a host of diverse disease that encompassacquired conditions such as cancer, cardiovascular diseaseand arthritis as well as monogenic diseases through genereplacement strategies. In theory the concept has seemedrelatively simply; in practice, however, gene therapy isextremely complex, both technically and clinically. Itrequires a multifaceted approach involving identificationof suitable therapeutic gene(s), identification of a suitablegene delivery vehicle together with the availability ofsatisfactory pre-clinical models in which to evaluate thepotential benefit of the gene therapeutic approach,particularly against alternative pharmacological therapies,if available. The issue of long-term safety of gene therapyapproaches is still unclear. To date, major progress at theclinical level has been made in defined areas, particularcancer, cystic fibrosis, haemophilia and some vasculardiseases. These advances have not been without majordrawbacks. Tragic events involving high dose delivery ofadenoviral vectors to a patient on a gene therapy clinicaltrial for ornithine transcarbamylase (OTC) deficiency aswell as the evolution of leukaemia in severe combinedimmunodeficiency (SCID) patients involving retroviralvectors (Cavazzana-C et al, 2000; Somia et al, 2000; Fox2003) have highlighted safety issues relating to genedelivery vectors. In vascular diseases, successful genetherapy will require the following:Identification of the optimal transgene cassette.Expression systems vary considerably for different genetherapy applications. Traditionally strong viral promotershave been used to provide maximal levels of expression ina multitude of recipient cell types. However, it isbecoming increasing important to supply expressionselectively to individual cell types or in a regulatedmanner through inducible promoters (such as tetracyclinsystem (Gossen et al, 1992; Vigna et al, 2002) thuscircumventing potentially deleterious effects of transgeneexpression in non-target cell types. Additionally, viralpromoters, particularly the cytomegalovirus immediate135